Characteristics And Defining Features

Behavioral and Clinical Features

1. The THIP model. Animals demonstrate immobility and some vibrissal twitching. This model appears to be a generalized absence model based on electroclinical correlation; however, to date no pharmacologic data support this hypothesis, nor are there ontogeny data or data concerning possible thalamocortical mechanisms in the generation of these discharges. This model differs from others described in this review because THIP-induced absence-like seizures in rats are exacerbated by valproate (Vergnes et al., 1985).

2. The GHB model. The behavioral correlate of SWD is complete behavioral arrest with facial myoclonus and vib-rissal twitching. GHB-induced SWDs most similar to those seen in humans are produced by intravenous (IV) administration of GHB to prepubescent monkeys. In this animal, an IV dose of 200mg/kg of GHB results in 2.5 Hz SWDs associated with behavioral immobility, head drops, staring, pupillary dilation, eyelid fluttering, rhythmic eye movements, and stereotypical automatisms (Snead, 1978a). In the rat, a standard dose of 0.09ml (100mg) of GBL per kilogram given IP reliably produces onset of bilaterally synchronous SWDs within 2 to 5 minutes of GBL administration (Figure 1). The frequency of the SWD is 7 to 9 Hz. Associated with these hypersynchronous electro-graphic changes are behavioral arrest, facial myoclonus, and vibrissal twitching. Therefore this model meets the criteria outlined in Table 2 in that it is predictable, reproducible, and produces electrographic and behavioral events similar to the human condition. The GHB meets all the pharmacologic criteria (Snead, 1988) and involves thalamocortical circuitry (Banerjee et al., 1993). An additional advantage of the GHB model is that it affords control of pharmacokinetic variables in any pharmacologic study in that the concentration of GBL and GHB can be determined in the brain and the kinetics is known (Snead, 1991).

3. The low-dose PTZ model. This model would seem to meet all the criteria set forth in Table 2. A dose of 20mg/kg of PTZ results in bursts of bilaterally synchronous SWDs with a frequency of about 7 to 9 Hz. The behavior seen in the PTZ animal is exactly the same as that described for GHB-treated animals, and it too meets pharmacologic criteria (Snead, 1988).

4. The AY-9944 model. This is a model of spontaneous, recurrent, atypical absence seizures. Clinically, atypical absence seizures are more complex than typical absence seizures. They present with a clinical behavioral change that

FIGURE 1 A: Baseline electrocorticogram (ECoG) recordings in controls are characterized by 35 to 50uV, 7 to 11 Hz intermingled 6 to 9Hz oscillations in awake resting conditions. B: The ECoG recording 5 minutes following 100mg/kg GBL illustrates two consecutive high-amplitude 7 to 9 Hz bilaterally synchronous SWDs. The ictal behavior during SWD consisted of frozen stare, vibrissal twitching, and facial myoclonus with complete behavioral arrest. GBL, g-butyrolactone; LF-P, left frontal-parietal; RF-P, right frontal-parietal; SWDs, spike-and-wave discharges.

FIGURE 1 A: Baseline electrocorticogram (ECoG) recordings in controls are characterized by 35 to 50uV, 7 to 11 Hz intermingled 6 to 9Hz oscillations in awake resting conditions. B: The ECoG recording 5 minutes following 100mg/kg GBL illustrates two consecutive high-amplitude 7 to 9 Hz bilaterally synchronous SWDs. The ictal behavior during SWD consisted of frozen stare, vibrissal twitching, and facial myoclonus with complete behavioral arrest. GBL, g-butyrolactone; LF-P, left frontal-parietal; RF-P, right frontal-parietal; SWDs, spike-and-wave discharges.

is gradual in both onset and offset. During atypical absence seizures children retain some ability for purposeful movement and speech but with fogging of consciousness. The ictal EEG discharge in atypical absence seizures is slower than the 3 Hz that characterizes typical absence seizures, and it is not time-locked with the ictal behavior (Figure 2). Similarly, the AY9944 model shows a gradual onset and offset of ictal behavior and the ability to move purposefully during the seizures. Also reminiscent of the human condition, the ictal EEG discharge in the AY 9944 model is not time-locked with the ictal behavior, and it is slower in frequency than the epileptiform activity that characterizes typical absence seizures (Cortez et al., 2001). The phenotypic expression of atypical absence seizures in the AY 9944 model is highly significant because there is a major difference in outcome in children with typical compared with atypical absence seizures. Children with typical absence seizures have a good outcome and are spared any cognitive deficit, perhaps because of the limitation of the SWDs to the thalamocorti-cal circuitry. In distinct contrast, atypical absence seizures are associated with a severely abnormal cognitive and neu-rodevelopmental outcome in children (Nolan et al., 2004). Therefore, whether absence seizures are typical or atypical is a critical predictor of outcome in children with absence epilepsy. The AY 9944 model also shows evidence of cognitive impairment (Chan et al., 2004) and thus represents a well-characterized model of atypical absence seizures that can be used to investigate mechanistic reasons for why atypical absence seizures confer such a poor long-term outcome on children afflicted by this disorder.

5. The MAM-AY model. The behavioral and EEG features of the MAM-AY model are exactly the same as the AY

model. The difference is that the MAM-AY treated rat is a model of medically refractory atypical absence seizures, whereas the AY model responds to ethosuximide and val-proic acid (Serbanescu et al., 2004).

Seizure Severity (Racine or Modified Racine Scale)

The original rating scale of convulsive seizures presented by Racine in (1972a, b) was based on amygdala kindling and may not be applicable to kindling from other sites (Mclntyre et al., 2002).

Status Epilepticus (SE): Defining the Type of SE

There are few data concerning animal models of generalized nonconvulsive status epilepticus (NCSE) (Hosford, 1999). Experimentally, PTZ-induced generalized NCSE leads to a subtle deficit-in-place learning in rats, with no demonstrable long-term behavioral effects on spatial learning or sensorimotor function. However, at 1 week follow-up, these animals showed an increase in absence seizures in response to a repeat dose of PTZ compared with controls. There was no detectable brain damage, but rats continued to show neuronal functional changes characterized by alteration of electrical excitability of neural circuits after generalized NCSE (Erdogan et al., 2004; Wong et al., 2003). This finding is consistent with our previous report on repeated induction of GHB absence seizures (Hu et al., 2001a) and is distinct from the pilocarpine-induced NCSE, which is associated with attendant seizure-related brain damage (Krsek et al., 2001).

FIGURE 2 Baseline electrocorticogram (ECoG) recordings at postnatal day 60 AY-9944-treated rat illustrates the spontaneous bilaterally synchronous and high-amplitude 5- to 6-Hz SSWDs from cortex, thalamus, and hippocampal monopolar electrodes. The ictal behavior during SSWDs consisted of frozen stare, vibrissal twitching, and facial myoclonus with the ability to move during seizures. L, left; R, right; Ctx, cortex; Th, thalamus; Hi, hippocampus. SSWD, slow spike-and-wave discharges.

FIGURE 2 Baseline electrocorticogram (ECoG) recordings at postnatal day 60 AY-9944-treated rat illustrates the spontaneous bilaterally synchronous and high-amplitude 5- to 6-Hz SSWDs from cortex, thalamus, and hippocampal monopolar electrodes. The ictal behavior during SSWDs consisted of frozen stare, vibrissal twitching, and facial myoclonus with the ability to move during seizures. L, left; R, right; Ctx, cortex; Th, thalamus; Hi, hippocampus. SSWD, slow spike-and-wave discharges.

Forebrain Versus Hindbrain Seizures

Experimental absence seizures are constrained within thalamocortical circuitry and therefore are exclusively fore-brain seizures (Banerjee et al., 1993; Crunelli and Leresche, 2002; McCormick and Bal, 1997; Snead et al., 1999, 2000; Vergnes et al., 1990). As mentioned, increasing doses of the GABAaR antagonists bicuculline, picrotoxin, or pentylenetetrazole results in a dose-dependent phenomenon in which the lower doses first involve thalamocortical circuitry and produce absence-like seizures. Intermediate doses involve more widely distributed forebrain structures and produce forelimb clonus. Higher doses result in recruitment of brainstem circuitry with resultant tonic seizures. One could postulate that the same progression is present in Lennox-Gastaut syndrome, which is characterized by atypical absence (thalamocortical-hippocampal circuitry), clonic and myoclonic seizures (widespread neocortical circuitry), and tonic seizures (brainstem circuitry).

Electrographic and Electroencephalogric Features

McQueen and Woodbury (1975) attempted to produce bilaterally synchronous SWDs in the electrocorticogram of rats by using several experimental paradigms, including administration of pentylenetetrazole, picrotoxin, conjugated estrogens, and bilateral intracerebral cobalt implants. In their hands, no pharmacologic modality produced consistent bilaterally synchronous SWDs. The authors concluded, therefore, that the rodent was not suitable for any detailed study of the pathophysiology of SWD. However, that same year, spontaneous SWDs were first reported in rodent (Vanderwolf, 1975) and have been described in a number of strains of rats since that time (Buzsaki et al., 1988; Kaplan, 1985, 1990; Kleinlogel, 1985). With a few notable excep tions (Cox et al., 1997), rats do not usually generate 3 Hz SWDs; rather, the usual frequency of SWDs in the THIP, PTZ, and GHB models range from 7 to 9 Hz, whereas the SSWD frequency in the AY-9944 and MAM-AY models is 4 to 6 Hz (Table 4).

Neuropathology

Cell Loss

There are no reports on cell loss in pharmacologic models of generalized absence seizures comparable to those reported in the other models of status that are associated with severe hippocampal damage. The reason for this is probably related to the fact that absence seizures are constrained within thalamocortical circuitry.

Reactive Gliosis

To date, there are no reports on reactive gliosis following experimental absence seizures of any kind except for the recently described two-hit MAM-AY9944 model of refractory atypical absence epilepsy (Serbanescu et al., 2004). However, further pathological and molecular investigation of the morphologic changes observed in animal models of limbic epilepsy may provide further understanding of the chronicity and refractoriness observed in MAM-atypical absence seizure model because atypical absence seizures appear to involve limbic as well as thalamocortical circuitry (Chan et al., 2004; Cortez et al., 2001).

Plasticity

Cognitive abnormalities are reported to occur in patients with atypical absence seizures (Nolan et al., 2004) and in the AY model (Chan et al., 2004). In typical absence seizures

TABLE 4 Electrographic features pharmacological models

Models Latency (minutes) Frequency (Hz) Seizure Duration (Sec/Hour) Human Seizure Type References

Acute PCL LDPTZ GHB THIP

Chronic

Genetic GAERS WAG/Rij

Acquired AY-9944 MAM-AY

Was this article helpful?

0 0

Post a comment